This Program Project supports the San Antonio Family Heart Study (SAFHS), the first comprehension genetic epidemiological study of atherosclerosis and its correlates in Mexican Americans. It's long-term goal is to detect, characterize, map, and identify new polymorphic genes that influence variation in susceptibility to cardiovascular disease (CVD). More than 1,400 members of 41 extended Mexican American families were recruited without regard to disease status and examined during the first grant period (SAFHS1), and 859 family members were recalled during the current grant period(SAFHS2). Genotyping of all family members for 414 markers in a 10 centimorgan map will be complete by the end of the current grant period. Data from nearly 500 members of 10 large families (Pedigree Set A) have been used to successfully detect and map quantitative trait loci (QTLs) influencing leptin, fat mass, BMI, insulin, 2 hour glucose, LDL-3-HDL-C, HDL2a unesterified cholesterol, several measures of median HDL particle size, P-selectin, and VCAM-1. For regions with the strongest evidence for linkage, additional markers are being typed for use in finer scale mapping strategies. With the completion of the genome scan for the remaining family members, SAFHS investigators are poised to exploit the valuable resource created during the past 10 years. For two of the most promising findings, an effort will be launched to identify the functional polymorphisms accounting for linkage signals for leptin and HDL2a in chromosomal regions with strong positional candidates genes (POMC and LIPC, respectively). QTLs for phenotypes for which strong signals have not yet been detected will mapped and chacterized in the larger data set. The most promising leads will be pursued by refining linkage signals, characterizing interactions and pleiotropy, assessing associations with candidate genes polymorphisms, and seeking to identify the QTS. Novel phenotypes of the adipo-insular axis and phenotypes related to inflammation and oxidative stress also will be targeted. These new phenotypes, as well as glucose, insulin, leptin, total and HDL cholesterol, and lipoprotein size phenotypes, will be assessed in a recall of 950 family members. Taking advantage of 5- and 10-year longitudinal data, SAFHS investigators will seek to map genes that influence age-related changes in CVD risk factors.